Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study
Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study
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DOI：
10.1016/j.phrs.2020.104950
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发表时间：
2020-08-01
影响因子：
9.3
通讯作者：
Santus, Pierachille
中科院分区：
文献类型：
--
作者：
Viecca, Maurizio;Radovanovic, Dejan;Santus, Pierachille
严重冠状病毒引起的疾病-2019 （Covid-19）患者通常由于肺泡受累和内皮功能障碍而出现低氧血症，导致肺毛细血管形成微血栓。低氧血症和血栓形成前素质都与更严重的疾病和死亡风险增加有关。迄今为止，缺乏治疗这种疾病的具体适应症。这是一项单中心、研究者发起、同情使用、概念验证、病例对照的IIb期研究（NCT04368377），在意大利米兰L. Sacco大学医院的中级呼吸护理病房进行。我们的目的是探讨抗血小板治疗对合并高凝血症的重症Covid-19患者动脉氧合和临床结局的影响。我们连续招募了5例实验室确诊的SARS-CoV-2感染、需要头盔持续气道正压通气（CPAP）的严重呼吸衰竭、双侧肺浸润和确定为d -二聚体bbb30的血栓前状态的患者。年龄、Ddimer值、SOFA评分相匹配的患者5例为对照组。在标准护理之外，接受治疗的患者接受25 μ g/Kg体重的替罗非班大剂量输注，然后以每分钟0.15 μ g/Kg体重的速度连续输注48小时。在使用替罗非班之前，患者接受乙酰水杨酸250 mg输注和氯吡格雷300 mg口服；两种药物都以每天75毫克的剂量持续30天。在住院期间给予氟达哌宁x2.5 mg/天皮下注射。根据当地标准操作程序，所有对照组均接受预防性或治疗性肝素治疗。治疗后24、48小时和7天，治疗患者的a - 02梯度平均（SD）持续下降，分别为-32.6 mmHg （61.9, P = 0.154）、-52.4 mmHg （59.4, P = 0.016）和-151.1 mmHg （56.6, P = 0.011；与对照组相比，P = 0.047）。Pa02/Fi02比值在24、48 h和7 d后分别升高52 mmHg （50, P = 0.172）、64 mmHg （47, P = 0.040）和112 mmHg （51, P = 0.036）。除1例患者外，所有患者均在3天后成功脱离CPAP。而对于对照组来说，情况并非如此。未观察到重大不良事件。抗血小板治疗可有效改善Covid-19合并严重呼吸衰竭患者的通气/灌注比。其作用可能是通过预防和干扰肺毛细血管血栓形成、调节巨核细胞功能和血小板粘附来维持的。迫切需要随机临床试验来证实这些结果。
Patients affected by severe coronavirus induced disease-2019 (Covid-19) often experience hypoxemia due to alveolar involvement and endothelial dysfunction, which leads to the formation of micro thrombi in the pulmonary capillary vessels. Both hypoxemia and a prothrombotic diathesis have been associated with more severe disease and increased risk of death. To date, specific indications to treat this condition are lacking.This was a single center, investigator initiated, compassionate use, proof of concept, case control, phase IIb study (NCT04368377) conducted in the Intermediate Respiratory Care Unit of L. Sacco University Hospital in Milano, Italy. Our objective was to explore the effects of the administration of anti-platelet therapy on arterial oxygenation and clinical outcomes in patients with severe Covid-19 with hypercoagulability.We enrolled five consecutive patients with laboratory confirmed SARS-CoV-2 infection, severe respiratory failure requiring helmet continuous positive airway pressure (CPAP), bilateral pulmonary infiltrates and a prothrombotic state identified as a D-dimer > 3 times the upper limit of normal. Five patients matched for age, Ddimer value and SOFA score formed the control group.Beyond standard of care, treated patients received 25 mu g/Kg/body weight tirofiban as bolus infusion, followed by a continuous infusion of 0.15 mu g/Kg/body weight per minute for 48 hours. Before tirofiban, patients received acetylsalicylic acid 250 mg infusion and oral clopidogrel 300 mg; both were continued at a dose of 75 mg daily for 30 days. Fondaparinux2.5 mg/day sub-cutaneous was given for the duration of the hospital stay. All controls were receiving prophylactic or therapeutic dose heparin, according to local standard operating procedures.Treated patients consistently experienced a mean (SD) reduction in A-a 02 gradient of -32.6 mmHg (61.9, P = 0.154), -52.4 mmHg (59.4, P = 0.016) and -151.1 mmHg (56.6, P = 0.011; P = 0.047 vs. controls) at 24, 48 hours and 7 days after treatment. Pa02/Fi02 ratio increased by 52 mmHg (50, P = 0.172), 64 mmHg (47, P = 0.040) and 112 mmHg (51, P = 0.036) after 24, 48 hours and 7 days, respectively. All patients but one were successfully weaned from CPAP after 3 days. This was not true for the control group. No major adverse events were observed.Antiplatelet therapy might be effective in improving the ventilation/perfusion ratio in Covid-19 patients with severe respiratory failure. The effects might be sustained by the prevention and interference on forming clots in lung capillary vessels and by modulating megakaryocytes' function and platelet adhesion. Randomized clinical trials are urgently needed to confirm these results.